Pharmaceutical production

In addition to our work on artemisinin, the Keasling laboratory is determining the metabolic pathway responsible for synthesis of prostratin, a 20-carbon phorbol ester with anti-viral properties. This molecule, derived from the bark of the mamala tree, was first discovered by Samoan healers and used to treat hepatitis. Recently, this molecule has been shown to have anti-HIV properties. By determining the metabolic pathway responsible for its synthesis in the mamala tree and engineering microorganisms to produce it, we will have developed an environmentally friendly production system for the drug if it is approved.

Similarly, we are working on determining the missing steps in the Taxol pathway, a taxane diterpenoid used as an anti-cancer drug and produced by all species of the genus Taxus, the yew trees. Current methods of production still rely on a plant source, resulting in low and unstable yield, high production costs, and unwanted byproducts. Determining the metabolic pathway for its production should similarly lead to an engineered microbe to be used for production.

While many natural products have become important pharmaceuticals, most natural products are not ideal for treating human disease. To broaden the product range of metabolic pathways and develop alternatives to natural products that might be more suitable for treating human disease, we are examining and changing the substrate range of cytochrome P450 hydoxylases to oxygenate a broader range of terpenes than they would normally oxidize and to do so in different positions on the molecule than they would naturally oxidize. The resulting oxidized terpenes might be precursors for production of pharmaceuticals or other products.